Breaking down the barriers

As a molecular biologist, Dr Nikola Bowden appreciates the importance
of scientific process, but as a researcher she has also learnt the value of
trusting her instincts. It was a gut feeling that prompted Bowden to pursue a
line of research that has consequently shifted the central dogma around the
role of DNA repair in melanoma development and provided a possible explanation
for why the disease is largely resistant to chemotherapy.

Bowden's breakthrough paper on nucleotide expression repair
in melanoma, published in the journal Cancer
Research in 2010, was the first to report on the relationship between DNA
repair pathways and chemotherapy resistance in melanoma.

"Chemotherapy usually works by attacking the DNA of a cancer
cell and damaging it so badly that it dies," Bowden explains. "Normally, the
DNA repair pathway in a cell will either fix damage, as it does when we get
sunburnt, or 'tell' a cell to die when the damage is extreme. But in melanoma
this pathway is dysfunctional, so chemotherapy has little or no effect and the cancerous
cells continue to accumulate damage and grow."

Because the same DNA repair pathway fixes damage to cells
from sunlight, Bowden is now pursuing a hypothesis that dysfunction in the
pathway could increase susceptibility to melanoma. Her research project is supported
by the Cure Cancer Australia Foundation and the Hunter Medical Research
Institute (HMRI).

"I was surprised to find that no one had pursued this line
of research before – it is almost as if it had been dismissed because it was
too obvious," Bowden remarks.

The researcher's interest in the DNA repair process was
sparked by studies she conducted into the rare childhood skin cancer xeroderma
pigmentosum (XP), first as a biomedical science Honours student at the University
of Newcastle then later as a postdoctoral research fellow.

"XP sufferers have an inherited mutation in their DNA repair
pathway and can develop melanomas from very little exposure to sunlight. There
are 12 genes that can carry this mutation and I always suspected that those
genes may be involved in adult melanoma as well. So now we are looking at those
genes in adults and testing their response to UV light exposure."

Bowden has developed some high-powered international
collaborations and counts among her mentors Dr Javed Khan, a leading figure from
the US National Cancer Institute. She spent six months at the Institute in 2010,
at Khan's invitation, where she learnt 'next-generation' DNA sequencing
techniques, which allow her to study the entire human genome at once. She has
established an important working relationship with pathologists at the John
Hunter Hospital and has contributed her skills in whole genome analysis to
collaborations with colleagues investigating a range of diseases including leukaemia,
schizophrenia, breast cancer, asthma and multiple sclerosis.

Bowden aims to develop diagnostic tests that will identify people
at high risk of melanoma and also assist doctors in predicting how a diagnosed cancer
is likely to respond to different drug therapies, so they can tailor patient treatment
accordingly. She is already witnessing the benefits of this style of
personalised medicine. In one puzzling cancer case, on which she was asked to
consult, she was able to determine from DNA testing that a patient had two
distinct primary tumours, rather than a primary and a secondary. The finding
had important implications for the way the cancer was treated.

"Research can be a long road so it is very encouraging to
see that sort of immediate benefit in your work," Bowden says. "I would like to think the genetic analysis
we are developing in melanoma will be regularly used in practice within the
next five years, so we can give patients a better idea from the outset of the
treatment likely to help them most."

Career Summary

Biography

Dr Nikola Bowden was appointed at the University of Newcastle in 2006 as the inaugural NBN Telethon childhood cancer post-doctoral fellow. Subsequent to this in 2008 she was awarded a Gladys M. Brawn memorial post-doctoral fellowship from the Faculty of Health, University of Newcastle. In January 2009 Dr Bowden was appointed as a Lecturer in the School of Biomedical Sciences & Pharmacy and was awarded an NH&MRC training (post-doctoral) fellowship which she commenced in October 2009. Since 2006, Dr Bowden has developed a research interest with the overall aim of delivering personalised diagnosis and treatment to patients with cancer, with a more focused interest in investigating DNA repair in melanoma. Dr Bowden's research has been funded through a nationally competitive fellowship and grants from the NH&MRC, Cure Cancer Australia Foundation and Cancer Australia, respectively. Dr Bowden collaborates with Dr Daniel Catchpoole at the Children’s Hospital at Westmead and has international collaborations with Prof James Cleaver from University of California San Francisco (USA) and Dr Javed Khan from the National Cancer Institute and National Institutes of Health (USA). Dr Bowden has obtained over $1,000,000 in funding, published 22 articles in international peer-reviewed journals and have presented her research over 60 times at international and national conferences. Dr Bowden currently supervises 4 research higher degree PhD students. Dr Bowden was awarded the University of Newcastle Young Alumni Award in 2011 and was part of a collaboration awarded the Schizophrenia Research Institute Research Paper Award in 2008 and was the recipient of the 2007 Hunter Children's Research Foundation (HCRF) Award for Research Excellence for her research into the DNA repair and skin cancer disorder, Xeroderma Pigmentosum, and childhood acute lymphoblastic leukaemia. In 2006, she was awarded the Hunter Medical Research Institute (HMRI) PULSE Education Prize, an award presented to an outstanding early career researcher. Dr Bowden has been an invited reviewer for the international funding body Medical Research Council (UK), and many international journals.

Research ExpertiseBelow is a summary of my current research projects: Nucleotide Excision Repair Gene Expression in Melanoma: My main research program is investigating the role of DNA repair in cancer. The results of a pilot study into deficient DNA repair in melanoma have been published in the journal Cancer Research. The publication of this manuscript represents a shift in the central dogma surrounding DNA repair and melanoma. To date there has been a central belief that DNA repair is not involved in development of melanoma. The results of our study have now confirmed the hypothesis that a deficiency in DNA repair is indeed a feature of melanoma and may be the reason why melanomas develop after excessive sun exposure and why melanomas do not respond to common chemotherapeutic agents. The major outcome of this research program will be a biological explanation for why excessive sunlight exposure results in melanomagenesis and why melanomas do not respond to common DNA-damaging chemotherapeutic agents, two of the most elusive features of melanoma. In addition, I collaborate with Dr Ricardo Vilain and Dr Stephen Braye from the Hunter Area Pathology Service (HAPS) Anatomocal Pathology department to utilise formalin-fixed paraffin embedded (FFPE) melanoma tissue collected and stored for diagnostic purposes. This tissue represents a very large cohort of individuals from the hunter region with melanoma and allows for retrospective analysis of clinical data such as disease recurrence, response to treatment and survival. Another major advantage of using this tissue is that it requires no direct participation from patients with melanoma thus lessening the burden of research on clinicians and patients. This collaboration was established in 2009 and the preliminary results of several projects have been presented at the 7th and 8th International Congress of the Society for Melanoma Research (2010 & 2011).

Children with the recessive genetic disorder Xeroderma Pigmentosum (XP) have extreme sensitivity to UV-light, a 10,000-fold increase in skin cancers from age 2 and rarely live bey... [more]

Children with the recessive genetic disorder Xeroderma Pigmentosum (XP) have extreme sensitivity to UV-light, a 10,000-fold increase in skin cancers from age 2 and rarely live beyond 30 years. There are seven genetic subgroups of XP, which are all resultant of pathogenic mutations in genes in the nucleotide excision repair (NER) pathway and a XP variant resultant of a mutation in translesion synthesis, POLH. The clinical symptoms and severity of the disease is varied across the subgroups, which does not correlate with the functional position of the affected protein in the NER pathway. The aim of this study was to further understand the biology of XP subgroups, particularly those that manifest with neurological symptoms. Whole genome gene expression profiling of fibroblasts from each XP complementation group was assessed before and after UV-light exposure. The biological pathways with altered gene expression after UV-light exposure were distinct for each subtype and contained oncogenic related functions such as perturbation of cell cycle, apoptosis, proliferation and differentiation. Patients from the subgroups XP-B and XP-F were the only subgroups to have transcripts associated with neuronal activity altered after UV-light exposure. This study will assist in furthering our understanding of the different subtypes of XP which will lead to better diagnosis, treatment and management of the disease.

News

University of Newcastle researcher Dr Nikola Bowden is investigating a
DNA repair protein that is implicated in ovarian cancer tumours becoming
resistant to chemotherapy, with hopes of eventually developing a
prognostic test and more tailored treatments.

Dr Nikola Bowden

Position

Research FellowSchool of Biomedical Sciences and PharmacyFaculty of Health and Medicine